Strategies in Regenerative Medicine (eBook)

Integrating Biology with Materials Design

Matteo Santin (Herausgeber)

eBook Download: PDF

2009 | 2009
XII, 605 Seiten
Springer New York (Verlag)
978-0-387-74660-9 (ISBN)

Infos

The profound transformations occurred in our modern age have been made possible by the unique combination of new technologies. Among them, me- cine has completely changed our perception of life. Longevity has been signi- cantly extended and linked to new lifestyles. The negative impact that pathologies and ageing have always had on the quality of our life is now mitigated by the availability of treatments daily applied to many individuals worldwide. For many years, pharmacological and surgical treatments have been supported by the introduction of biomedical devices. Biomedical implants have played a key role in the development of these treatments and achieved the objective of replacing tissue and organ structures and functionalities. Gra- ally, the scientific and clinical communities have understood that replacement could be improved by materials able to interact with the tissues and to parti- pate in their metabolism and functions. This approach soon led to biomedical implants with improved clinical performances, but also to a new aspiration; rather than replacing damaged tissues and organs scientists and clinicians nowadays aim at their partial or complete regeneration. As a consequence of this ambition, the disciplines of tissue engineering and regenerative medicine have recently emerged. It is the dawn of a fascinating era where scientists from various disciplines, clinicians, and industry will need to intensify their col- borative efforts to provide our society with new and affordable solutions.

Inhalt

Preface 6
Contents 8
Contributors 10
The Editor’s Profile 15
Introduction: History of Regenerative Medicine 17
1.1 Introduction 17
1.2 The Pioneers 18
1.2.1 The Pioneers of Tissue Engineering and of Clinical Tissue Regeneration 18
1.2.2 The Pioneers of the Biomimicking Biomaterials Science 20
1.2.3 The Pioneers of the Tissue Engineering Science 23
1.3 The Birth of Regenerative Medicine 24
1.3.1 Early Clinical Applications 25
1.3.2 Commercialization Efforts 25
1.4 Challenges 27
Questions 27
References 28
Soft Tissues Characteristics and Strategies for Their Replacement and Regeneration 30
2.1 Composition-Structure-Properties of Soft Tissues: Introduction 31
2.2 Tendons and Ligaments 32
2.2.1 Composition and Structure 32
2.2.2 Mechanical Properties 33
2.3 Skin 35
2.3.1 Composition and Structure 35
2.3.2 Mechanical Properties 37
2.4 Arteries 40
2.4.1 Composition and Structure 40
2.4.2 Mechanical Properties 42
2.5 Cartilage 43
2.5.1 Composition and Structure 43
2.5.2 Mechanical Properties 46
2.6 Soft Tissue Replacements 49
2.6.1 Introduction 49
2.7 Ligament Prostheses 49
2.8 Skin Replacements 53
2.8.1 Skin Substitutes for Wound Cover 55
2.8.1.1 Biobranereg 55
2.8.1.2 Transcytereg 55
2.8.1.3 Apligrafreg 55
2.8.1.4 Dermagraftreg 55
2.8.2 Skin Substitutes for Wound Closure 56
2.8.2.1 Allodermreg 56
2.8.2.2 Integrareg 56
2.8.2.3 Cultured Epidermal Autograft (CEA) 56
2.8.2.4 Cultured Skin Substitutes (CSS) 57
2.9 Vascular Grafts 57
2.10 Cartilage Replacement 60
2.10.1 Joint Resurfacing 60
2.10.2 Biological Autograft 60
2.10.3 Total Joint Replacement 61
2.10.4 Tissue Engineered Constructs 61
Questions/Exercises 64
References 65
Biomaterials for Tissue Engineering of Hard Tissues 70
3.1 Function and Structure of Bone 71
3.2 Bone Engineering 71
3.2.1 Cells 72
3.2.2 Growth Factors 73
3.2.3 Scaffolds 74
3.3 Synthetic Material for Bone Repair Biodegradable Scaffolds 75
3.3.1 Bioactive Glass Ceramics 79
3.4 Natural Biodegradable Scaffolds for Bone Repair 81
3.5 Bio-Stable Materials 84
3.5.1 Natural: Hydroxyapatite 84
3.5.1.1 Bioceramic Coatings 85
3.5.1.2 Bioactive Ceramics 86
3.5.2 Synthetic Materials 87
3.5.2.1 Metals 87
Most Important Applications of SMA Devices in Biomedicine are the 90
3.5.2.2 Polymers 90
3.6 Composite Materials 92
3.6.1 Why Porosity is Needed? 95
3.6.2 PLA-Glasses 96
3.6.3 Collagen-Cement Composites 96
3.6.4 Hyaluronic Acid-collagen 96
3.6.5 Coated Scaffolds 97
3.6.6 Self Assembly Nanofibers for Biomineralization 97
3.7 Characterization Methods 98
3.7.1 Porosity 98
3.7.2 Microstructure 98
3.7.3 Surface Properties 99
3.7.4 Dynamic and Static Contact Angles Measurement 100
3.7.5 Mechanical Properties 100
3.7.6 Z Potential 100
3.7.7 Solubility of the Different Compounds 101
3.7.8 Adsorbed Protein Amount 101
3.7.9 Statistical Study 101
3.8 Bone Disease Society Impact and Market 102
3.8.1 Incidence of Bone Fractures 102
3.8.2 Business Market on Bone Tissue Engineering 102
Questions/Exercises 104
References 105
Biomimetic and Bio-responsive Materials in Regenerative Medicine 112
4.1 Introduction to Biomimetic Materials 113
4.2 Biomimetic Rationale and Design Principles 114
4.3 Mammalian Tissue and Natural ECM as Design Guides 117
4.3.1 ECM Composition and Structure 117
4.3.1.1 ECM Types and Function 117
4.3.1.2 ECM Structure 119
4.3.1.3 ECM Components 119
4.3.1.4 ECM Receptors 120
4.4 Tissue Dynamics 121
4.4.1 ECM Metabolism 121
4.4.2 Enzymatic Catabolism 123
4.5 Strategies for Biomimetic Tissue Regeneration 124
4.5.1 Matrices and Tissue Conduction 125
4.5.2 Growth Factors and Cellular Induction 126
4.5.3 Cells and Tissue Neogenesis 128
4.6 Building Biomimetic Materials 130
4.6.1 Starting Materials 130
4.6.2 Natural Biopolymers 130
4.6.3 Synthetic Polymers 132
4.6.4 Hybrid and Composite Materials 133
4.7 Biomimetic Material Synthesis 133
4.7.1 Macromers 133
4.7.2 Conjugation Methods 134
4.7.3 In Situ Material Synthesis 134
4.7.4 Free Radical Polymerization 135
4.7.5 Step-Growth Polymerization 135
4.7.6 Physical Association 136
4.7.7 Molecular Self-Assembly 137
4.8 Biomimetic Elements 137
4.8.1 Cell Adhesion Domains 137
4.8.1.1 Cellular Adhesion 137
4.8.1.2 Conjugation of Cell-Binding Motifs to Polymers 140
4.8.1.3 Self-Assembling Nanofibers Featuring Cell-Binding Motifs 142
4.8.1.4 Reactive Macromers Containing Cell-Binding Motifs 142
4.8.1.5 Parameters and Effects of Cell-Binding Motif Incorporation 143
4.8.2 Substrate Mechanics 146
4.8.3 Enzymatic Degradability 148
4.8.3.1 Engineering Degradability into Biomaterials 148
4.8.3.2 Methods of Imparting Enzymatic Degradability 150
4.8.3.3 Effects of Enzymatic Degradability 150
4.8.4 Growth Factor Activity 152
4.8.4.1 Considerations for Growth Factor Incorporation 152
4.8.4.2 Growth Factor Encapsulation 152
4.8.4.3 Growth Factor Conjugation 154
4.8.4.4 Heparin and Heparin-Binding Incorporation 156
4.8.4.5 Multiple Growth Factor Release Profiles 158
4.9 Neglected Topics in Biomimetic Materials 159
Questions/Exercises 160
Top Ten Original Publications from the Last Decade 161
References 161
Clinical Approaches to Skin Regeneration 170
5.1 Introduction 170
5.2 Normal Skin Structure and Function 171
5.2.1 Epidermis 172
5.2.2 Basement Membrane 172
5.2.3 Dermis 172
5.2.4 Cellular Component of the Dermis 173
5.3 Mechanisms of Skin Loss 174
5.3.1 Pathological Damage 174
5.3.1.1 Wound Depth 174
5.3.2 Surgical Damage 175
5.4 Healing of Wounds 176
5.4.1 Wound Closure Categories 176
5.4.1.1 Primary Healing 177
5.4.1.2 Secondary Healing 177
5.4.1.3 Tertiary Healing 177
5.4.2 Wound Healing Process 177
5.4.2.1 Hemostasis and Inflammation 178
5.4.2.2 Proliferative Phase 179
5.4.2.3 Scar Maturation or the Remodeling Phase 180
5.5 Problems of Natural Wound Healing 180
5.6 Current Clinical Approaches to Wound Healing 181
5.7 Development of Novel Approaches to Skin Regeneration 184
5.7.1 Surgical Use of Cultured Keratinocytes in Burns Patients 184
5.7.2 Commercially Available Skin Substitutes 189
5.7.3 Clinical Application of Skin Substitutes 190
Questions/Exercises 200
References 201
Angiogenesis in Development, Disease, and Regeneration 203
6.1 Introduction 204
6.2 Developmental Angiogenesis 204
6.3 Angiogenesis in Adult Life 205
6.4 Endothelial Cell Specialization 207
6.5 Molecular Regulators of Angiogenesis 209
6.5.1 Vascular Endothelial Growth Factor 211
6.5.2 Hypoxia-Inducible Factor 1 212
6.5.3 Angiopoietins and Tie Receptors 213
6.5.4 Platelet Derived Growth Factor (PDGF) Family 214
6.6 Structure of the Blood Vessel 215
6.7 Angiogenesis and Tissue Development 216
6.7.1 Pancreas 216
6.7.2 Liver 216
6.7.3 Nervous System 217
6.7.4 Adipose Tissue 218
6.8 Angiogenesis in Pathological Conditions 220
6.8.1 Angiogenesis in Tumors 221
6.8.2 Psoriasis 227
6.8.3 Ocular Neovascularization 227
6.8.4 Atherosclerosis 227
6.9 Tools to Study Angiogenesis 228
6.9.1 Matrigel Tube Formation Assay 229
6.9.2 Cornea Pocket Assay 229
6.9.3 Chamber Models 229
6.10 Angiogenesis in Regeneration 230
6.10.1 Growth Factors Based Pro-angiogenic Therapy 233
6.10.2 Cell-based Pro-angiogenic Therapy 234
6.11 Concluding Remarks 236
Questions/Exercises 236
References 237
Tissue Engineering of Small- and Large- Diameter Blood Vessels 244
7.1 Introduction 244
7.2 Historical Overview - Development of Artificial Vascular Grafts 245
7.3 State of the Art - Currently Used Synthetic Vascular Grafts 246
7.3.1 Dacron (PET) 246
7.3.2 Expanded Polytetrafluorethylene (ePTFE) 246
7.3.3 Polyurethanes (PU) 247
7.3.4 Limitations of the Currently Used Vascular Grafts 247
7.3.4.1 Patency Rates 248
7.3.4.2 Potential for Regeneration, Remodeling, and Growth 249
7.4 Requirements for the ‘‘Ideal’’ Vascular Replacement 249
7.5 Tissue Engineering - A Promising Concept for ‘‘Ideal’’ Vascular Replacements 251
7.5.1 The Golden Standard - Architecture and Characteristics of Native Blood Vessels 251
7.5.1.1 General structure 251
7.5.1.2 Arteries 253
7.5.1.3 Veins 253
7.5.2 Tissue Engineering of Vascular Grafts - Strategies and Approaches 253
7.5.2.1 Scaffolds for the Engineering of Vascular Grafts 254
Natural scaffolds 254
Permanent Synthetic Scaffolds 255
Biodegradable Synthetic Scaffolds 255
7.5.2.2 Cells 257
Vascular-Derived Cells 257
Bone Marrow-Derived Cells 257
Blood-Derived Cells 258
Umbilical Cord-Derived Cells 258
7.5.3 How to Match the Mechanical Requirements of Native Tissue 259
7.5.4 Tissue Engineering of Small-Diameter Vessels - In Vitro and In Vivo Studies 260
7.5.5 Tissue Engineering of Large-diameter Vessels - In Vitro and In Vivo Studies 263
7.5.6 First Clinical Experiences 264
7.6 Limitations and Future Perspectives 265
7.7 Summary 266
Questions/Exercises 267
References 267
Pancreas Biology, Pathology, and Tissue Engineering 274
8.1 Introduction 274
8.2 Pancreas Biology 276
8.2.1 Islets of Langerhans 276
8.3 Pathology 277
8.3.1 Pathogenesis and beta-cell Dysfunction in Diabetes 277
8.3.2 Pathogenesis of Diabetes and Mechanisms of beta-Cell Death 278
8.3.2.1 Type 1 diabetes 278
8.3.2.2 Type 2 diabetes 280
8.3.2.3 Thiazolidinediones (TZDs) 280
8.3.2.4 GLP-1 and Dipeptidyl Peptidase IV (DPP-IV) Inhibitors 281
8.4 Tissue Engineering: Generating Replacement beta-cells 282
8.4.1 Islet Transplantation 282
8.4.2 Engineering Replacement beta-cells 283
8.4.3 Adult Stem Cells: Pancreas 284
8.4.4 Liver Cells 286
8.4.5 Bone Marrow 287
8.4.6 Embryonic Stem Cells 288
8.5 Summary 290
Questions/Exercises 290
References 291
The Holy Grail of Hepatocyte Culturing and Therapeutic Use 295
9.1 Introduction 296
9.2 Legal Aspects of Cell Therapy in Future 296
9.3 Hepatocyte Isolation and Culture 297
9.4 Clinical Hepatocyte Transplantation 301
9.5 Hepatocytes Used in Drug Development - Metabolism and Toxicology 303
9.6 Hepatocytes Generated by Stem Cell Technology 304
9.6.1 Can Human Hepatocytes Be Produced by Stem Cell Technology? An Overview 304
9.6.2 Transdifferentiation of Extrahepatic Cells to Hepatocytes? First Evidence Pointing towards Bone Marrow Cells 306
9.6.3 Cell Fusion or Transdifferentiation? A Question of Potential Clinical Relevance 307
9.6.4 The Discovery of ‘‘Fusogenic Cells’’ in Mouse Bone Marrow 308
9.6.5 Elegant Reporter Studies Differentiate Between Cell Fusion and Real Differentiation 309
9.6.6 Fate of Human Stem and Precursor Cells in Livers of Mice 312
9.6.7 Transdifferentiation of Extrahepatic Human Stem Cells to Hepatocytes In Vitro? 314
9.6.8 Quantitative Analyses Comparing Stem Cell Derived Cells with Primary Hepatocytes 318
9.6.9 5-Years Perspective 320
Questions/Exercises 324
Ten Key Publications 325
References 326
Peripheral Nerve Injury, Repair, and Regeneration 333
10.1 Introduction 333
10.2 Current Clinical Methods of Nerve Repair and Reconstruction 335
10.2.1 Direct Co-aption (Neurorrhaphy) 336
10.2.1.1 Epineurial Repair 336
10.2.1.2 Grouped Fascicular Repair 336
10.2.1.3 Fascicular Repair 337
10.2.2 Nerve Autografts 337
10.2.3 Nerve Transfers 338
10.2.4 Nerve Guidance Tubes 338
10.2.4.1 Silicone Tubes and the Development of Clinically Approved Nerve Guidance Tubes 338
10.2.4.2 Future Biotechnological Applications of Nerve Guidance Tubes: Administration of Neurotrophic Factors 339
10.3 Emerging Technologies for Nerve Repair 340
10.3.1 Electric Fields to Aid and Guide Nerve Growth 340
10.3.2 Potential Cellular Machinery Affected by Electric Field Effects 341
10.3.3 Wound Potentials and Spinal Cord Repair 342
10.4 Use of Stem Cells to Aid Regeneration 343
10.4.1 Mechanical Guidance of Regeneration 344
10.4.2 Microchip Technologies Under Development 344
10.4.3 Technologies for Aiding Repair 344
10.4.3.1 Controlled Delivery of Trophic Factors 344
10.4.3.2 Microscopic Guidance Techniques 345
10.4.4 Non-Repair Technologies: Prosthetics 346
10.4.4.1 Capacitive Interfacing with Transistors and Nanowires 346
10.4.4.2 Current Based Interfacing 346
10.4.4.3 Partial Regeneration Through Sieve Electrodes 347
10.5 Summary 347
Questions/Exercises 347
References 348
Therapeutic Strategies in Ocular Tissue Regeneration: The Role of Stem Cells 353
11.1 Introduction 354
11.2 Historical Perspective 355
11.2.1 Healing, Repair, Regeneration, and Reconstitution 355
11.2.2 Evolution-Two Levels of Regeneration 355
11.2.3 ‘‘Three Type of Cells’’ - The Old Theory 356
11.3 Regenerative Medicine of the Eye 356
11.4 Stem Cells 357
11.4.1 Stem Cell Hierarchy 357
11.4.2 Embryonic Stem Cells 357
11.4.3 Sources of Embryonic Stem Cells 358
11.4.3.1 Blastocyst 358
11.4.3.2 Somatic Cell Nuclear Transfer Techniques (SCNT) 358
11.4.3.3 Pre-Implantation Diagnostic Screening 359
11.4.4 Adult Stem Cells 359
11.4.5 Stem Cells from Umbilical Cord Blood 359
11.4.6 What Determines the Fate of Stem Cells? 359
11.4.7 Stem Cell Niche 360
11.4.8 How to Identify Stem Cells? Stem Cell Markers 361
11.4.9 How Safe are Stem Cells for Cell Therapy? 361
11.5 Genetic Regulations of Stem Cells 361
11.5.1 Genes Controlling Embryonic Stem Cells 362
11.5.2 Regulation of Ocular Stem Cells - Pax6 362
11.5.3 Transdifferentiation, Metaplasia, and Re-Programming of Cell Fate 363
11.6 Ocular Stem Cells 364
11.6.1 Corneal Epithelial Stem Cells 364
11.6.2 Endothelial Stem Cells 365
11.6.3 Retinal Stem Cells 365
11.6.4 Stem Cells in New Blood Vessels 365
11.7 Disorders of Stem Cells in the Eye 366
11.8 Strategies of Ocular Regeneration 366
11.8.1 Limitation of Tissue Damage 366
11.8.1.1 Inflammation and Tissue Damage 366
11.8.1.2 Treatments to Limit Tissue Damage 368
11.8.1.3 Modulation by NF-kappaB 368
11.8.2 Ocular Regeneration with Stem Cells 369
11.8.2.1 Keratolimbal Transplantation 370
11.8.2.2 Ex vivo Limbal Stem Cell expansion 371
11.8.2.3 Regeneration of the Retina 371
11.9 Gene Therapy 372
11.10 The Future 373
Questions/Exercises 373
References 374
Cartilage Development, Physiology, Pathologies, and Regeneration 378
12.1 Introduction 378
12.2 Articular Cartilage Development, Composition, and Structure 379
12.2.1 Development 379
12.2.2 Composition 380
12.2.3 Structure 382
12.3 Pathology, Pathophysiology, Pharmacological Therapies of Osteoarthritis 383
12.3.1 Arthritis 383
12.3.2 Osteoarthritis Pathology 383
12.3.3 Risk Factors for Osteoarthritis 384
12.3.4 Pathophysiology of Osteoarthritis 385
12.3.5 Pharmacological Therapies for Osteoarthritis 386
12.4 Cartilage Repair and Regeneration 386
12.4.1 Articular Cartilage Defects and Spontaneous Repair 386
12.4.2 Current Operative Strategies for Articular Cartilage Repair 388
12.4.3 Mesenchymal Stem Cells (MSCs) 390
12.4.4 Chondrogenic Differentiation of MSCs 390
12.4.5 Tissue Engineering 392
12.4.6 Experimental Approaches for Articular Cartilage Tissue Engineering 393
12.5 Conclusions 397
Questions/Exercises 397
References 398
Basic Science and Clinical Strategies for Articular Cartilage Regeneration/Repair 405
13.1 Introduction 405
13.2 Articular Cartilage and its Repair 406
13.2.1 Normal Articular Cartilage: Basic Science of Structure, Biology, and Function 407
13.2.2 The Vital Role of Growth Factors in Normal Articular Cartilage Matrix Biosynthesis 408
13.2.3 Optimal Chondrocyte Density in Cartilage 410
13.2.4 Clinical Findings of Cartilage Structure Functionality 412
13.3 Hyaline Articular Cartilage Response to Injury 413
13.4 Treatment Options for Cartilage Injuries 415
13.5 Autologous Chondrocyte Implantation 418
13.5.1 ACI Surgical Procedure and Technique 419
13.6 Key Questions About ACI 422
13.7 Conclusions: The Clinicians’ View on Treatments for Articular Cartilage Repair 434
References 436
Bone Biology: Development and Regeneration Mechanisms in Physiological and Pathological Conditions 441
14.1 Introduction 441
14.2 Macroscopic and Microscopic Structure of Bone 442
14.3 Differentiation and Functional Activities of Osteoblastic Cells 443
14.4 Bone Remodeling 444
14.5 Bone Development and Growth 445
14.6 Bone Repair and Regeneration 446
14.7 Bone Morphogenetic Proteins and Transforming Growth Factor-betas 448
14.8 Bone Tissue Engineering by BMP 451
14.9 Angiogenesis and Bone Regeneration 453
14.10 Bone Formation in Pathologic Conditions 453
14.10.1 Bone Tumors 453
14.10.2 Myositis Ossificans and Fibrodysplasia Ossificans Progressiva (FOP) 454
14.10.3 Ossification of the Spinal Ligaments 455
14.11 Conclusions 455
Questions 456
References 456
Clinical Applications of Bone Tissue Engineering 459
15.1 Introduction 459
15.2 The Clinical Problem 462
15.3 Stem Cells in Orthopedic Therapy 463
15.4 Biomaterials as Biomimetic Scaffolds 466
15.5 Clinical Applications in Orthopedics 469
15.6 Conclusions 470
Questions/Exercises 472
References 472
Conclusions: Towards High-Performance and Industrially Sustainable Tissue Engineering Products 477
16.1 Introduction 477
16.2 From Interfacial to Complete Tissue Regeneration 478
16.2.1 Development of Non-Invasive Implantation Procedures 480
16.2.1.1 Injectable Biomaterials 481
16.2.1.2 Self-Assembling Biomolecules 482
16.2.1.3 Nanostructured Biomaterials 482
16.2.2 Controlling and Exploiting the Inflammatory Response 483
16.2.2.1 Control of Macrophage Activation 484
16.2.2.2 Exploitation of the Host Response 485
16.2.3 Biochemical Cues Analogues 486
16.2.3.1 Bioligands Analogues 486
16.2.3.2 Growth Factors Analogues 487
16.2.3.3 Drugs and Bioactive Natural Molecules 488
16.2.4 Biostructural Cues Analogues 491
16.3 Complete Tissue and Organ Regeneration 494
16.3.1 Technical Issues in Tissue and Organ Regeneration 495
16.3.1.1 Biomaterials and Bioreactors 495
Technical Issues Associated to the Use of Biomimetic and Bioresponsive Biomaterials 495
Technical Issues Associated to the Use of Bioreactors 496
Technical Issues Associated to the Use of Cells 496
16.4 Regulatory Issues 497
16.4.1 The American Federal Law 497
16.4.2 The EC Consultation Process and Regulation 498
16.5 Towards the Exploitation of Tissue Engineering Products 498
16.5.1 Bioactive Biomaterials Market 499
16.5.2 Stem Cells Market 499
16.6 Overall Conclusions 500
References 500
Index 504

Produkt-Details

• Erscheint lt. Verlag: 28.2.2009
• Zusatzinfo: XII, 605 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Pflege
• Themenwelt: Medizin / Pharmazie ► Physiotherapie / Ergotherapie ► Orthopädie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik ► Bauwesen
• Themenwelt: Technik ► Maschinenbau
• Themenwelt: Technik ► Medizintechnik
• Schlagworte: angiogenesis • Biomaterial • biomedical device • Blood vessel • Bone • Cartilage • Cement • Databases • Physiology • Regenerative medicine • Stent • tissue • Tissue engineering • tissue regeneration
• ISBN-10: 0-387-74660-9 / 0387746609
• ISBN-13: 978-0-387-74660-9 / 9780387746609